The primary goal of the proposed research is to empirically and quantitatively test the hypothesis that combinations of four biologically active components of Cannabis sativa act synergistically to protect against the development of pain in two rodent models: chemotherapy-induced neuropathic pain and pain associated with dental pulp exposure. In addition, effects of these Cannabis components on morphine analgesia and will also be assessed. Cannabis contains over 100 phytocannabinoids as well as several terpene compounds which are also biologically active. As stated in RFT-AT-19-008, while a growing body of literature suggests that Cannabis may have analgesic properties, the psychoactive effects of the phytocannabinoid ?9-tetrahydrocannabinol (THC) limit its utility, calling for an investigation into the therapeutic potential of additional phytocannabinoids and terpenes found in the plant. Our laboratory has been studying the anti-neuropathic efficacy of the non- psychoactive phytocannabinoid cannabidiol (CBD) for over a decade. In addition to CBD, the minor cannabinoid cannabigerol (CBG), the acid form of THC THCA, and the terpene beta-caryophyllene (?-CP), are receiving increasing interest by clinicians as analgesics and/or anti-inflammatory agents. We have also recently demonstrated that ?-CP prevents the development of mechanical sensitivity in a rat model of dental pain. Importantly, so-called ?entourage effects? of Cannabis constituents are anecdotally discussed at length, but empirical data are woefully lacking, including the potential for synergistic interactions outside of THC. We determined that CBD acts synergistically with THC to attenuate mechanical allodynia associated with paclitaxel administration, while attenuating the antinociceptive effects of morphine on thermal sensitivity. Testing for such interactive effects requires rigorous dose response testing and analysis across single and combined agents, and these requirements increase with the number of agents to be combined. Animal modeling to test unique interactive effects of several Cannabis constituents provides a uniquely effective contribution to translational medicine, as executing such studies in a clinical setting is immensely more challenging and expensive. In the current proposal we will determine the efficacy of CBD, CBG, THCA, and ?-CP alone and in combination on tactile allodynia and other pain-related behaviors in males and females. We will also determine the interactive effects of CBD, CBG, THCA, and ?-CP with morphine on acute antinociceptive and visceral pain. At the completion of behavioral testing, complementary cellular and molecular approaches will be utilized to also characterize effects of single and combined agents on markers of pain and inflammation. The assembled team has the expertise and collaborative relationship to ensure the feasibility and achievement of the proposed project. The overall impact of the project will be to provide empirically-derived evidence for key components of Cannabis representing non-psychoactive single and/or combined for the treatment of acute and chronic pain.